Human lung tissue resident memory T cells in health and disease
Introduction
The human lung experiences continuous and direct exposure to environmental and microbial antigens – both innocuous and pathogenic – through inhalation and oropharyngeal aspiration. Consequently, acute and chronic lower respiratory tract infections, including influenza and mycobacterial tuberculosis, remain the leading cause of death in developing countries and contribute to over five million global deaths annually [1]. To maintain tissue homeostasis and protection from pathogens in the context of these recurrent challenges, the lung contains heterogeneous populations of innate and adaptive immune cells, many of which are tissue resident. Deficiencies in the immunologic response to inhaled pathogens can result in life threatening infections, sepsis, and even cardiovascular shock. Conversely, dysregulation in the interactions between the resident immune cells and cellular components of the lung can lead to acute respiratory distress syndrome [2], or more insidious chronic inflammatory diseases such as pulmonary fibrosis [3] and asthma [4]. Understanding the mechanisms by which lung immune cells interact with and function in health and disease is essential to begin to develop therapies to modulate these interactions in situ.
The major immune cell populations in the lungs include macrophages and dendritic cells as the prevalent innate cells, and CD4+ and CD8+ T lymphocytes as the predominant adaptive immune cells (Figure 1). Alveolar macrophages (AM) comprise the majority of lung macrophages [5]. Mouse AM are critical for protection from infection and are implicated in dysregulations involved in lung inflammation and fibrosis [6,7]. Mouse and human AM can be delineated into subsets based on their location and migration properties (Figure 1); intravital imaging in murine studies detail how sessile macrophages remain adherent to the epithelial layer of the alveoli and work to attenuate immune responses, providing much of the regulatory signals preventing lung injury during an inflammatory response to antigen, while non-sessile alveolar macrophages which continually surveil the airspace and initiate inflammatory responses to inhaled or aspirated pathogens [8,9•,10,11]. Therefore, resident innate cells in the lung are essential for tissue homeostasis and are involved in its breakdown in disease.
T cells become primed and activated in lymphoid tissues and migrate to the lung during responses to respiratory pathogens. A subset are found to persist as memory T cells after pathogen clearance. The lung was shown some time ago to contain predominant effector memory T cell (TEM) populations (CD45RA−, CD45RO+, CCR7−) [12, 13, 14], that were initially thought to represent a migrating, surveilling population. However, it is now clear that the majority of lung T cells persist as non-circulating tissue-resident memory T cells (TRM). TRM are now recognized as a distinct subset of TEM, present in multiple mucosal, barrier, lymphoid and peripheral tissues, and that TRM are difined by upregulation of CD69 and CD103 expression promoting tissue retention; notably, TRM have a unique transcription profile distinguishing them from circulating TEM [15,16]. Lung TRM were initially identified as CD4+T cells which were retained specifically in the lung in parabiosis studies, occupied specific niches around airways, and mediated optimal protective responses to influenza challenge [17,18•]. Lung CD8+ TRM are also generated following influenza infection and both CD4+ and CD8+ TRM can be established in intranasal vaccines and mediate cross-strain protection to heterosubtypic strains of influenza virus [19,20•]. Conversely, lung CD4+TRM generated in response to allergen exposure can mediate immunopathology and promote reactive airway disease [21,22•]. Mouse studies have therefore revealed a central role for TRM in multiple aspects of lung immunity.
The importance of TRM in lung immunity in mouse models has prompted extensive study into their potential role in human lung homeostasis and disease. Studying lung tissue in humans is challenging due to limited sampling opportunities. From patients, one can obtain surgical explants that have been removed due to lung cancer or other diseases, or biopsies obtained in disease diagnosis or monitoring. Bronchoalveolar lavage (BAL) are bronchoscope-directed washes of the airway and alveoli obtained both for clinical monitoring in infection and transplantation. Finally, obtaining lungs from organ donors that are not used for transplantation can provide a rich source of healthy tissue for studying all aspects of lung biology, from cells to genes to tissue organization [23].
Using these different sampling approaches, it is now established that the majority of both CD4+ and CD8+ T cells in the human lung are memory phenotype, and exhibit TRM phenotypes and transcriptional profiles [18•,24••,25•,26,27]. Human lung TRM are found throughout all regions of the respiratory tract including in the parenchyma, airways and associated lymph nodes [28•,29,30••] (Figure 1), suggesting roles in protection, immunosurveillance, and homeostasis. Here, we review the different properties of human lung TRM and recent studies in humans that reveal specific roles for human lung TRM in health and disease.
Section snippets
Defining human lung TRM
The vast majority of CD4+ and CD8+ T cells in the human lung have a TEM phenotype, but have a unique transcriptinal profile from circulating TEM, and substantial differences in protein expression and effector function. Notably, the majority of lung CD4+ and CD8+ TEM phenotype cells express the canonical TRM marker CD69 [24••,31]. CD69 is an early activation marker for T cell receptor signaling, but also exhibits retention functions through coordinated downregulation of sphingosine-1-phosphate
Human lung T cell heterogeneity with age
The composition and distribution of T cells in the lung vary with age; the most dynamic changes occur in early life, with relatively stable T cell subset frequencies over most of adult life as in other sites [43]. During infancy, naïve T cells (CCR7+CD45RA+) represent the predominant population in circulation and lungs along with substantial frequencies of regulatory T cells (Tregs, CD4+CD25hiCD127loFOXP3+), which provide a key role in promoting tolerance toward the numerous antigens
Lung TRM and protection against respiratory pathogens
Numerous studies in mouse models have established that the lung is enriched for TRM specific to multiple viral and bacterial pathogens generated by respiratory infection or vaccination. Lung CD4+ and CD8+ TRM are associated with heterosubtypic protection from subsequent influenza infection mediated, in part, by rapid IFNγ production following viral re-challenge [20•,47]. The resultant lung TRM accumulate and are maintained around airways [18•,48]. Furthermore, intranasal administration of a
TRM and anti-tumor immunity
A growing body of evidence suggests that a subset of tumor-associated lymphocytes in lung cancer may comprise TRM. Interestingly, the accumulation of CD103+ CD4+ and CD8+ T cells in primary non-small cell lung cancer was found to be a predictor of more favorable outcome, including increased survival [58•]. CD8+ tumor infiltrating lymphocytes (TIL) expressing CD103+ represent a clonally expanded population of tumor-reactive T cells, and express multiple core TRM markers including CD49a, CXCR6,
Lung TRM and immunopathology
TRM have been implicated in both the pathogenesis of and protection from chronic inflammatory diseases involving multiple mucosal surfaces, skin, and the synovium, including inflammatory bowel disease [62•], psoriasis [63], and juvenile arthritis [64•]. In a mouse model of house dust mite (HDM) exposure, mouse airways developed a biased population of HDM-specific CD4+ TRM which had a predominant Th2 phenotype and contributed to airway resistance [21,22•]. In another study, CD8+ TRM generated
Conclusions
The human lung predominantly contains CD4+ and CD8+ TRM that persist in stable frequencies for decades of human life. Recent studies in mouse models and in human samples reveal an important role for lung TRM in the defense against inhaled pathogens, in maintaining tissue homeostasis in the face of diverse antigens encountered through respiration, and may also be important in surveillance for tumors and persistent viruses. Lung TRM can also promote pathologic inflammation, inducing chronic
Conflict of interest statement
Nothing declared.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
Funding: This work was supported by the National Institutes of Health (grant numbers HL116136 and HL145547 to D.L.F.) and a Parker B. Francis Foundation fellowship (to M.E.S.).
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2022, GeneCitation Excerpt :In lambs, lung volume increases sharply in the first two months of life, then flattens out, but the number of alveoli increases only triple during this time (Davies et al. 1988). Lung tissue contains a large number of alveolar macrophages and tissue resident memory T cells (Trm), which are very active in phagocytosis, immunity and secretion (Snyder and Farber 2019). Alveolar macrophages participated in anti-inflammatory and tissue repair what induces the platelet-activating factor (PAF), with associated suppression of pro-inflammatory cytokines and chemokines (Allard, Panariti, and Martin 2018).
Heterogeneity of tissue resident memory T cells
2022, Immunology LettersCitation Excerpt :The role of AhR in human TRM cells remains to be determined, although there are indications that it may make a similar contribution to TRM cells as in mice [46]. In sum, many transcription factors, including Hobit, Blimp1, AhR, Tbet, and Eomes, are known mediators promoting TRM cell formation, with altered expression levels relative to those found in circulating memory T cells [5, 36, 47]. The transcription factors required for human TRM cells remain to be fully elucidated [5, 16, 36, 47].